As a progressive neurodegenerative disorder characterized by accelerated neuronal cell death leading to dementia, Alzheimer's disease (AD) is one of the Nation's greatest medical, social and economic challenges. However, despite the urgency and abundance of research in the field there is still no cure for AD. While there is currently no consensus on the mechanism of AD, the majority of drug discovery efforts target the first of two defining neuropathological features of AD, amyloid-beta (Abeta) containing plaques, whereas far fewer studies target the neurofibrillary tangles (NFTs) composed of polymerized tau protein. However, recent studies strongly correlate NFT formation to the degree of dementia in AD and have ignited interest in furthering our understanding of tau pathology. Based on preliminary studies in animal and fish models, small molecules that inhibit or reverse the formation of NFTs caused by tau polymerization could provide the basis for a new class of AD therapeutics. Neuronautics Inc. (NNI) is developing AD therapeutics that act by inhibiting or reversing NFT formation. We have screened 35,000 compounds and identified eight classes that inhibit tau polymerization in vitro with IC-5Os in the nanomolar range. Our extensive research on two compounds and their analogs - NNI3 and NNI5 belonging to a class of benzothiazole derivatives looks very promising. They have IC-50's below 100 nM. In vivo treatment of the sea lamprey neuronal cell model of neurofibrillary pathology expressing human tau isoforms- htau23 and htau40 with NNI3 and its analogs significantly reduced neurodegeneration. We also have favorable preliminary indications of brain penetration in mice. In addition, we have confirmed that these drugs do not interfere with normal tau function even at drug concentrations as high as 100 mu M in vitro. There have also been preliminary indications that NNI3 and NNI5 may be inhibiting tau filament formation by two different mechanisms. In this study we propose to perform pharmacokinetic studies and in vivo testing of the eight NNI lead drug candidates in animal and cell models of tauopathy. RELEVANCE: With this work we hope to prove the hypothesis that neurodegeneration seen in AD can be cured by inhibiting or reversing the formation of tau tangles. This project will enable NNI to complete studies showing biological activities and the safety profile of its lead compounds in vivo. We hope that by the end of this study we will have at least two compounds ready for Phase-l clinical trials. [unreadable] [unreadable] [unreadable] [unreadable]